• October 6, 2006, iPLEDGE: An update to iPLEDGE that will eliminate one element of the program.
• August 12, 2005, iPLEDGE: Approval of a strengthened risk management program, called iPLEDGE, for Accutane and generic isotretinoin.

Note from the National Guideline Clearinghouse (NGC) and the Institute for Clinical Systems Improvement (ICSI): In addition to updating their clinical guidance, ICSI has developed a new format for all guidelines. Key additions and changes include: combination of the annotation and discussion section; the addition of "Key Points" at the beginning of most annotations; the inclusion of references supporting the recommendations; and a complete list of references in the Supporting Evidence section of the guideline. For a description of what has changed since the previous version of this guidance, refer to Summary of Changes -- May - 2006.

The recommendations for acne management are presented in the form of an algorithm with 10 components, accompanied by detailed annotations. An algorithm is provided for Acne Management; clinical highlights and selected annotations (numbered to correspond with the algorithm) follow.

Class of evidence (A-D, M, R, X) and conclusion grade (I-III, Not Assignable) definitions are repeated at the end of the "Major Recommendations" field.

Clinical Highlights

• Patient perception of improvement is the best measure of successful treatment. (Annotation #4)
• Although acne is not a life threatening disease, the clinician must be aware of potentially debilitating psychosocial effects. (Annotation #4)
• Treatment with both a topical retinoid and a topical antibiotic has been found to be an effective course of treatment. (Annotation #5)
• Customize a treatment plan that the patient will be able to follow according to his/her needs. (Annotations #6, 8)
• The patient needs to understand that acne may get worse before it gets better. It typically takes eight weeks of treatment before a response is noted. (Annotation #7)
• Isotretinoin therapy is highly regulated. (Annotation #9)

Algorithm Annotations

1. Patient Presents for Treatment of Acne/Provider Observes Acne

   When presented with acne in office visit scheduled for other reason, identify comfort with condition and desire for treatment.

2. Review Possible Contributing Factors

   Hormonal

   Signs of androgen excess would include:

   • Precocious puberty
   • Hirsutism

   Possible causes of androgen excess would include:

   • Polycystic ovary disease
   • Adrenal tumor
   • Ovarian tumor
   • Pituitary tumor

   Mechanical

   On occasions physical occlusion may contribute to acne. For example: hockey masks; oil-based cosmetics (although most cosmetics today are water based).

   Evidence supporting this recommendation is of classes: D, R

   Medications

   There are many medications that may contribute to the development of acne. In addition to treating the acne, consideration may be given to discontinuing these medications. Refer to the original guideline document for a list of medications that may contribute to the development of acne.

   Evidence supporting this recommendation is of classes: D, R

3. Assess Objective Severity of Acne

   Acne severity is the most important clinical diagnostic tool in studies reviewed. For simplification, the guideline developer is following the Agency for Healthcare Research and Quality's (AHRQ) recommendation to divide acne into three severity grades: mild, moderate, and severe. There are a number of other ways of grading acne that are used clinically and in research. None, however, is universally accepted. Additionally, psychological impact or the presence of scarring may play a role in assigning a severity grade to the patient.

   The following diagnostic tool was designed as a guideline for three lesion counts on the face but may be applicable to grading the severity of acne on the trunk as well.

   1. Mild Acne:

      Mild acne is characterized by predominance of comedones (fewer than 20), or fewer than 15 inflammatory papules, or a comedone/papule count of fewer than 30 on the face.

   2. Moderate Acne:

      Moderate acne predominantly exhibits papules and pustules (about 15-50 lesions) with comedones and rare cysts. Total lesion (comedone, papule, pustule) count may range from 30 to 125 on the face.

   3. Severe Acne:

      Severe acne is characterized primarily with the presence of inflammatory nodules and cysts. Also present are comedones, papules, and pustules or total lesion count of greater than 125 on the face.

      Definitions:

      • Closed Comedone (whitehead): non-inflamed (non-red) follicular opening containing a keratotic plug with a thin overlying epidermal membrane
      • Open Comedone (blackhead): non-inflamed (non-red) follicular opening containing a keratotic plug that appears black
      • Papule: small round to oval red elevation of the skin (1-4 mm)
      • Pustule: resembles a papule with a central pocket of pus
      • Nodule/Cyst: poorly marginated red tender, sometimes draining 0.2- to 3.0-cm indurated mass in the skin

   Evidence supporting this recommendation is of classes: M, R

4. Assess Psychosocial Impact of Acne

   It is important to assess the psychosocial effect of acne. Studies using "quality of life" surveys show a variety of significant impacts, most frequently, anxiety and depression. Decreased self-esteem, social withdrawal, anger, conduct disorders, and decreased employability have been reported in other studies. The clinical severity of the acne does not always predict the severity of the psychosocial impacts. Effective treatment of acne can decrease these negative effects.

   If significant psychosocial effects are present, consider a more aggressive initial treatment (such as combination therapy and closer follow-up) than might be indicated by the objectively observed severity alone. Patient perception of improvement is the best measure of successful treatment.

   Evidence supporting this recommendation is of classes: C, D, R

5. Choose Treatment Plan

   There are multiple treatment modalities that have been demonstrated effective in the treatment of acne. [Conclusion Grade I: See Conclusion Grading Worksheet A- Annotation #5 (Choose Treatment Plan) in the original guideline document.]

   Resistance to antibiotics is rising but does not appear to decrease effectiveness of treatment. [Conclusion Grade II: See Conclusion Grading Worksheet B -- Annotation #5 (Resistance to Antibiotics) in the original guideline document.]

   When initiating treatment it is important to consider the goals of therapy. Treatment goals should include:

   • Achieving clearance of acne
   • Prevention of scarring
   • Learning to cope with psychological stress resulting from the acne

   Considerations:

   • Patient skin type (oily to dry)
     • for very oily skin consider a gel or solution
     • for very dry skin choose creams or lotions
   • If more than one topical is being used (for example a retinoid and a topical antibiotic), have patient apply one in the morning and the other at night.
   • If multiple agents are used, they should be from different classes. For example, a benzoyl peroxide and a topical antibiotic.
   • Customize treatment to enhance adherence. For example, can the patient reach their back to apply the product? Importance of avoiding food, especially dairy products, one hour before or two hours after taking tetracycline.

   Relative Cost Value

   Costs for treatment modalities may vary significantly and should be considered in treatment selection. Refer to the original guideline document for cost ranges and key for a 30-day supply.

   1. Topical Treatment of Acne

      An example of treatment for mild acne may include benzoyl peroxide, a topical antibiotic, or a combination product one to two times daily; or a topical retinoid once daily in addition to the above. See tables in this annotation in the original guideline document for description of medications.

      Over-the-counter Topical Products

      A wide variety of over-the-counter (OTC) topical products are available to the patient for self-treatment of acne. A complete listing is beyond the scope of this publication. The most common ingredient in OTC products is benzoyl peroxide in concentrations up to 10%. (Many of the expensive acne systems advertised contain benzoyl peroxide and offer no advantages over commercial products.) Salicylic acid in concentrations of 0.5% to 2% is a keratolytic found in many OTC acne products. Products may also contain glycolic acid (an alpha-hydroxy acid), sulfur, or resorcinol. When evaluating a new patient it is helpful to know which products they may have tried.

      Benzoyl Peroxide

      Benzoyl peroxide is available without a prescription in products such as Clearasil® and by prescription in the products listed in the original guideline document. It is also available in combination with antibiotics (see "Topical Antibiotics" table in the original guideline document).

      Topical Retinoids for Acne

      Topical retinoids (see "Topical Retinoids" table in the original guideline document) increase the turnover of follicular epithelial cells, promote drainage of comedones, and inhibit new comedone (blackhead, whitehead) formation. Topical retinoids are generally applied in the evening.

      Azelaic Acid

      Azelaic acid is a naturally occurring dicarboxylic acid which has been shown to be effective in reducing both inflammatory and non-inflammatory acne lesions (see "Azelaic Acid" table in the original guideline document.)

      Topical Antibiotics for Acne

      Propionibacterium acnes (P. acnes) is an anaerobic bacterium present within the pilosebaceous follicles. It is thought that this microorganism plays a role in acne-associated inflammation. The antibiotics used to treat acne have been shown to reduce colonization of P. acnes and may also possess direct anti-inflammatory effects. In-vitro resistance of P. acnes to commonly used antibiotics has been increasing but the clinical significance of this is uncertain. However, it has been recommended that antibiotics be used with either topical retinoids or benzoyl peroxide. (See "Single Drug Products" and "Combination Products" tables in the original guideline document.)

   2. Topical Treatment and Oral Antibiotics for Acne

      An example for moderate/severe acne may include examples listed in section 5a of the original guideline document with the addition of an oral antibiotic while continuing with the topical treatment. (See "First Line Antibiotics" and "Second Line Antibiotics" tables in the original guideline document for descriptions of products.)

      Antibiotics such as azithromycin and others are being used in acne but studies are preliminary and concrete recommendations regarding their use cannot be made at this time.

   Evidence supporting this recommendation is of classes: A, C, D, R

6. Patient Education

   Successful management of acne is dependent on a successful partnership between the health care team and the patient. Non-adherence is one of the biggest causes of treatment failure. Clear guidelines regarding treatment, possible adverse effects, and realistic expectations of treatment outcomes should be given to the patient to achieve the best possible outcome. Ongoing patient education, follow-up, encouragement, and maintaining a positive approach are vital. Because acne can be so devastating for many, early intervention with a proactive treatment plan may well prevent some of the long-term physical and psychosocial consequences.

   Myths and Facts

   An integral component of the prevention and treatment of acne is discussion of the facts and expulsion of the myths.

   MYTH: Any acne medication works immediately.

   FACT: It can take at least eight weeks of a prescribed treatment regimen for the patient to see any improvement. Acne may even get worse before it gets better.

   MYTH: Acne is a result of poor hygiene.

   FACT: As a result of this myth, people tend to overwash their skin, often scrubbing hard with abrasive cleansers. Cleaning the skin too often may aggravate acne and cause flare-ups. Wash face twice per day with a mild soap; pat dry, and use appropriate acne treatment. Acne is not caused by dirt or surface oil.

   MYTH: Washing many times a day will diminish acne.

   FACT: Under normal circumstances, wash no more than two times a day with mild soap and lukewarm, not very hot or very cold, water.

   MYTH: Washing with abrasive soaps, cleansing granules, astringents, vigorous scrubbing, or a buff puff will clear up acne on the face.

   FACT: Using your fingertips or a soft wash cloth is best.

   MYTH: Picking your acne will make it go away.

   FACT: This may cause scarring. Do not pick at acne lesions.

   MYTH: Once acne has cleared up, it will be gone forever.

   FACT: There is no cure for acne. If acne medication is discontinued, acne will probably flare.

   MYTH: Stress causes acne.

   FACT: Stress alone does not cause acne but may exacerbate psychological reaction to the acne. Acne is caused by overactive oil glands stimulated by androgens mixing with dead skin cells. This is particularly true during the teenage years when androgen production is at its highest.

   MYTH: Eating chocolate and sugar will cause acne.

   FACT: There is no evidence to support this. Certain foods may make some patients' acne worse and obviously should be avoided. No specific food has been proven to worsen acne. No diet has been shown to be beneficial.

   MYTH: Teenagers are the only ones affected by acne.

   FACT: Acne affects adults as well as children. The body produces androgens throughout life. The circumstances around adult acne may be a little different than in teens, particularly in women. Women between 18 and 40 years may have breakouts that occur most frequently when they are premenstrual.

   Evidence supporting this recommendation is of class: R

   Home Care Recommendations

   • Topical medications should be applied to dry skin.
   • Try to avoid abrasive soaps, cleansing granules, astringents, and vigorous scrubbing.
   • Under normal circumstances, wash no more than two times a day with your fingertips or a soft wash cloth.
   • Patients who are treated with acne medications often develop dry skin. Use fragrance-free, non-comedogenic, oil-free moisturizers. These moisturizers will not clog pores and therefore should not cause black- or whiteheads.
   • For patients who choose to use makeup to cover their acne lesions, a water-based, non-comedogenic makeup should be used. Avoid oil-based cosmetics. Use makeup sparingly.
   • Do not cover acne with bandages or tight fitting clothing.
   • If a topical retinoid or photosensitizing antibiotics are prescribed, recommend staying out of the sun as much as possible and stress the use of sunscreens.

   Evidence supporting this recommendation is of class: R

7. Follow-Up 6-12 Weeks/Satisfactory Response?

   There is no clear evidence to support a specific duration of any treatment for acne. However, clinical experience and clinical trials suggest that a minimum treatment period of 6 to 12 weeks is needed before an improvement will be noted in most patients.

8. Assess Outcome and Adherence

   Asking non-threatening, open-ended questions during patient interviews can be a useful method of assessing medication adherence. The interview should include probes for factors that contribute to non-adherence including adverse reactions, misunderstandings of asymptomatic or chronic disease treatment, depression, cognitive impairment, complex dosing regimens, and financial constraints.

   1. Assess the patient's knowledge of his/her medication and medical condition.
   2. Assess the patient's medication administration process.
   3. Assess the patient's barriers to adherence.

   To view sample assessment questions, refer to the original guideline document.

   Evidence supporting this recommendation is of class: R

9. Modify Treatment Plan

   Consider Different/Additional Medications

   It may be necessary to switch to a different class of topical acne medication. For example: if the patient is on a benzoyl peroxide product or a combination product and is not responding, consider switching to a once daily topical retinoid and a once daily topical anti-infective. For moderate to severe acne, consider adding an oral antibiotic or switching the current oral antibiotic. Selection is based on patient specific factors.

   Consider Adjunctive Therapy

   • Oral contraceptives

     The addition of combination oral contraceptives has been shown to be effective in the treatment of acne. [Conclusion Grade I: See Conclusion Grading Worksheet C - Annotation #9 (Oral Contraceptives) in the original guideline document.]

     Treatment with a combined oral contraceptive (estrogen and progestin) is an alternative for women who fail conventional acne therapies. Oral contraceptives are effective for the treatment of acne due to their androgen modulating properties. It is the estrogen component of combined oral contraceptives that reduces androgen production and decreases the amount of free and active testosterone by increasing the production of sex hormone binding globulin. Progestin-only oral contraceptives are not effective and may worsen acne. Responses may not be seen for 3 to 6 months, with some patients showing a flare of symptoms during early cycles. Although some progestins have exhibited androgenic properties during in vitro and animal studies, all combination oral contraceptives have antiandrogenic properties due to the estrogen component. To ensure adherence with therapy, the ideal product is one that has the lowest incidence of adverse effects for a particular patient. Products with Food and Drug Administration (FDA) indications for acne include Estrostep® and Ortho Tri-cyclen®.

   • Spironolactone

     Spironolactone is a medication primarily used in the treatment of hypertension. Due to its antiandrogenic effect, it has occasionally been used to treat adult-onset acne in women when other treatments have been ineffective. It is the effects of testosterone that are felt to be a contributing factor to the development of acne in adult females. The drug acts by blocking the effects of testosterone on the oil glands and hair follicles of the female patient. The result is a reduction in oil production that may lead to improvement of their acne. The optimal dosage varies, but ranges from 50 to 200 mg daily. Response may take two to three months*. The drug should not be used in pregnancy. Women of child-bearing age should use birth control methods while taking the medication. Side effects are rare, usually related to menstrual irregularity, mild gastrointestinal (GI) upset, or headache. The medication may be taken for one to two years with periodic rest periods.

     *Spironolactone can cause decreased sodium and increased potassium. Levels should be initially measured and carefully monitored at appropriate intervals.

   • Oral Retinoids

     Isotretinoin is the only oral retinoid approved for use in acne and is a well established teratogen. Although causality has not been determined for depression and suicide, this is an ongoing concern. In view of these factors its use is highly regulated by the FDA.

     Only providers registered with the iPLEDGE program may prescribe Isotretinoin. For information about this program conduct an internet search using: iPLEDGE program. This program is scheduled to start March 1, 2006 and replaces the existing System to Manage Accutane Related Teratogenicity (S.M.A.R.T.) program.

   • Intra-lesional injections

     There are rare circumstances in which you may consider injecting large acne cysts with a corticosteroid for short term cosmetic improvement. Each injection carries a risk of causing skin atrophy. Repeated injections are not recommended. The concentration of Triamcinolone varies from 2 to 10 mg/cc. The stock 10-, 25- or 40- mg/mL steroid suspension should be diluted with lidocaine and only enough injected through a 1-mL syringe with a 27- or 30- gauge needle to distend the cyst slightly (usually 0.025 mL to 0.1 mL).

   • Light Therapy

     There continue to be numerous studies about light treatment for acne, including blue light and photodynamic therapy with and without pretreatment with topical medications. At this time, the evidence is inadequate to make a recommendation about the efficacy and safety of these treatments.

   Consider Dermatology Referral

   Dermatologists treat all forms of acne, particularly severe cases. For those patients with severe inflammatory acne that has not improved with previously described medications, a retinoid, isotretinoin (Accutane), may be considered. Dermatologists may be helpful to guide you in any point of the algorithm.

   Evidence supporting this recommendation is of class: A, R

   For most current information regarding Isotretinoin:

   http://www.fda.gov/cder/drug/infopage/accutane/default.htm

10. Maintenance

    If stable on current topicals, continue treatment indefinitely.

    If stable on topical and systemic antibiotics, after clearance is achieved for 1 to 3 months consider tapering oral antibiotics and continue topicals indefinitely.

Definitions:

Conclusion Grades:

Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.

Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.

Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusions because of inconsistencies among the results from different studies or because of serious doubts about generalizability, bias, research design flaws, or inadequacy of sample sizes. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.

Grade Not Assignable: There is no evidence that directly supports or refutes the conclusion.

Classes of Research Reports:

1. Primary Reports of New Data Collection:

   Class A:

   • Randomized, controlled trial

   Class B:

   • Cohort study

   Class C:

   • Non-randomized trial with concurrent or historical controls
   • Case-control study
   • Study of sensitivity and specificity of a diagnostic test
   • Population-based descriptive study

   Class D:

   • Cross-sectional study
   • Case series
   • Case report
2. Reports that Synthesize or Reflect upon Collections of Primary Reports

   Class M:

   • Meta-analysis
   • Systematic review
   • Decision analysis
   • Cost-effectiveness analysis

   Class R:

   • Consensus statement
   • Consensus report
   • Narrative review

   Class X:

   • Medical opinion

A detailed and annotated clinical algorithm is provided for Acne Management.

For information about availability, see the "Availability of Companion Documents" and "Patient Resources" fields below.

ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; e-mail: icsi.info@icsi.org; Web site: www.icsi.org.

ICSI's conflict of interest policy and procedures are available for review on ICSI's website at www.icsi.org.

Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; Web site: www.icsi.org; e-mail: icsi.info@icsi.org.

• Acne management. Executive summary. Bloomington (MN): Institute for Clinical Systems Improvement, 2006 May. 1 p. Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.
• ICSI pocket guidelines. April 2006 edition. Bloomington (MN): Institute for Clinical Systems Improvement, 2006. 298 p.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; Web site: www.icsi.org; e-mail: icsi.info@icsi.org.

Electronic copies: Available in Portable Document Format (PDF) from the Institute for Clinical Systems Improvement (ICSI) Web site.

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